Schulte K M, Jonas C, Krebs R, Röher H D
Dept. of General Surgery and Trauma Surgery, Heinrich-Heine-University, Duesseldorf, Germany.
Horm Metab Res. 2000 Oct;32(10):390-400. doi: 10.1055/s-2007-978660.
Activin A belongs to the TGF-beta family of growth factors involved in control of tissue formation by growth inhibition and to a family of hormones involved in human reproduction. Serum levels of dimeric activin A display a sexual dimorphism with significantly higher circulating hormone concentrations in men than in women after menopause. Since goiter is far more frequent in women than in men, we investigated the role of this sex-related growth factor in the human thyroid. Primary cultures were obtained from 3 patients with goiter, and 4 with recurrent goiter. Activin A significantly inhibited the proliferation of human thyroid follicular epithelial cells in vitro in concentrations between 0.5 and 50 ng/ml and was almost as potent as TGFbeta-1. Analysis in native tissues from 12 normal thyroids, 16 goiters, and 5 Graves thyroids demonstrated mRNA expression of the activin subunit betaA, TGFbeta-receptor type I and II, activin receptors type I receptors alk2 and alk4, and activin type II receptors actRII and actRIIb. Isoform analysis of the major functional type I activin receptor alk4 revealed the full-length transcript SKR2-1 and transcripts for the partially truncated proteins SKR2-2 and SKR2-3 in normal thyroids and goiters. Semi-quantitative RT-PCR revealed a significant 2.5-fold decrease of mRNA for alk4-1 type I activin receptors in goiter as compared to normal thyroid (p < 0.05), whereas expression of the type II receptor actRII was unchanged. These data identify a novel growth inhibitory pathway by activin in the human thyroid. Down-regulation of activin receptor type lb in goiter hints towards end-organ changes which could contribute to deficient growth inhibition. These data provide a mechanistic model how the sexually dimorphic hormone activin A may protect males from goitrogenesis.
激活素A属于转化生长因子β家族的生长因子，通过生长抑制参与组织形成的控制，也属于参与人类生殖的激素家族。二聚体激活素A的血清水平表现出性别二态性，绝经后男性循环激素浓度显著高于女性。由于甲状腺肿在女性中比男性更常见，我们研究了这种与性别相关的生长因子在人类甲状腺中的作用。从3例甲状腺肿患者和4例复发性甲状腺肿患者中获取原代培养物。激活素A在0.5至50 ng/ml的浓度范围内显著抑制人甲状腺滤泡上皮细胞的体外增殖，其效力几乎与转化生长因子β-1相同。对12个正常甲状腺、16个甲状腺肿和5个格雷夫斯甲状腺的天然组织进行分析，结果显示激活素亚基βA、I型和II型转化生长因子β受体、I型激活素受体alk2和alk4以及II型激活素受体actRII和actRIIb的mRNA表达。对主要功能性I型激活素受体alk4的异构体分析显示，在正常甲状腺和甲状腺肿中存在全长转录本SKR2-1以及部分截短蛋白SKR2-2和SKR2-3的转录本。半定量逆转录-聚合酶链反应显示，与正常甲状腺相比，甲状腺肿中I型激活素受体alk4-1的mRNA显著降低2.5倍（p < 0.05），而II型受体actRII的表达未发生变化。这些数据确定了激活素在人类甲状腺中一种新的生长抑制途径。甲状腺肿中激活素I型受体lb的下调提示终末器官变化可能导致生长抑制不足。这些数据提供了一个机制模型，说明具有性别二态性的激素激活素A如何保护男性免受甲状腺肿的发生。
